Diabetic retinopathy is a diabetic complication which is caused by microangiopathy due to hyperglycemia, and the number of diabetic patients suffering from complicated diabetic retinopathy is increasing while the duration of diabetes becomes longer and longer. It is reported that not less than 80% of diabetic patients will suffer from retinopathy coincided with diabetes until two decades will have passed since the development of diabetes. Diabetic retinopathy develops to simple retinopathy, preproliferative retinopathy and proliferative retinopathy. In simple retinopathy, increase of vascular permeability, retinal edema, thickening of basement membrane, disorder in vascular endothelial cell, dropout of pericyte, etc. are observed. When deterioration of retinal potential (visual function) followed by vascular obstruction is observed, preproliferative retinopathy is diagnosed, which finally develops to proliferative retinopathy in which connective tissue membrane proliferation and neovascularization are observed. Proliferative retinopathy is, in some cases, accompanied by retinal detachment. The patients feel no subjective symptom to proliferative retinopathy. Therefore, when they have felt abnormality in the eyes, it is too late in many cases. Thus, it is very important to prevent or treat retinopathy or inhibit the development thereof in an early stage. Further, diabetic retinopathy is the primary cause of adult-onset blindness, and it induces a serious social problem in view of comfortable social life.
As the main treatments of diabetic retinopathy at present, photocoagulation using laser is done when neovascularization is observed in funduscopy, or a vitrectomy is done when diabetes has been developed with fibloblast membrane proliferation and retinal detachment observed. However, treatment by photocoagulation or a vitrectomy is in some cases impossible depending on the site affected by the disease, and in other cases, vision has not been restored even if the surgical treatment is succeeded. Under these circumstances, development of a pharmaceutical composition capable of treating diabetic retinopathy in an early stage is desired.
The compounds having angiotensin II antagonistic activities are known as agents for treating circulatory diseases such as hypertension, cardiac diseases (e.g., cardiomegaly, cardiac failure, cardiac infraction, etc.), cerebral hemorrhage, nephritis, etc. (refer to Japanese Unexamined Patent Publication No. 4-364171/1992 etc.). It is believed that the mechanism of action of such a compound would be actuated by inhibiting the binding of angiotensin II having a strong vasoconstriction to an angiotensin II receptor.
Diabetic patients have complicated hypertension at a higher frequency than non-diabetic patients, and hypertension is one of significantly critical factors for causing the onset and development of retinopathy. The diabetic patients with complicated retinopathy have higher blood levels of angiotensin-converting enzymes capable of producing angiotensin II having strong vasoconstriction than non-diabetic patients, and out of the diabetic patients, the patients having proliferative retinopathy tend to have higher blood levels of such enzymes than the patients without proliferative retinopathy.
Recently, researches for elucidating the pathology of diabetic retinopathy have been advanced, and it is believed that a vascular endothelial growth factor (VEGF), which exhibits potential endothelial cell growing action and vascular permeability increasing action, would induce proliferative retinopathy which is an terminal symptom of diabetic retinopathy, because of its physiological actions, an increase in the vitreous VEGF level of the patients with proliferative retinopathy, and increase of expression of VEGF on the retina of animal models. VEGF also has potential vascular permeability increasing action, and VEGF is considered to cause retinal edema observed in simple retinopathy or preproliferative retinopathy. It is reported that an individual renin-angiotensin system is found in the retina, and it becomes an evident that angiotensin II accelerates the production of VEGF in the retinal tissue. These facts suggest that the renin-angiotensin system is involved in diabetic retinopathy.